Volume 128
Editorial Board
G.V.R.Born,London P. Cuatrecasas, Ann Arbor, MI D. Ganten, Berlin H. Herken, Berlin K.L. Melmon, Stanford, CA K. Starke, Freiburg i. Br.
Springer Berlin Heidelberg New York Barcelona Budapest Hong Kong London Milan Paris Santa Clara Singapore Tokyo
Pharlllacotherapeutics of the Thyroid Gland
Contributors
J.W. Barlow, A.G. Burger, v.K.K. Chatterjee, T.C. Crowe J.A. Franklyn, E. Gaitan, G. Hennemann, J.H. Lazarus C-F. Lim, A.M. McGregor, CA. Meier, E. Milgrom M. Misrahi, S. Nagataki, M.F. Scanlon, M. El Sheikh J.R. Stockigt, A.D. Toft, D.J. Topliss, T.J. Visser A.P. Weetman, W.M. Wiersinga, N. Yokoyama
Editors
t Springer
PROFESSOR Dr. A.P. WEETMAN
Sir Arthur Hall Professor of Medicine The University of Sheffield Department of Medicine Clinical Sciences Centre Northern General Hospital Sheffield S5 7 AU United Kingdom
With 63 Figures and 29 Tables
ISBN -13:978-3-642-64519-8
PROFESSOR Dr. A. GROSSMAN
St. Bartholomew's Hospital Department of Endocrinology West Smithfield London EC1A 7BE United Kingdom
Pharmacotherapeutics of the thyroid gland 1 contributors, l.W. Barlow ... let aI.]: editors, A.P. Weetman and A. Grossman.
p. cm. - (Handbook of experimental pharmacology; v. 128) Includes bibliographical references and index. ISBN-13:978-3-642-64519-8 e-ISBN-13:978-3-642-60709-7 001: 10.1007/978-3-642-60709-7
1. Thyroid gland-Effect of drugs on. 2. Thyroid hormones-Physiological effect. 3. Thyroid antagonists-Physiological effect. I. Barlow, l.W. II. Weetman, Anthony P. III. Grossman, Ashley. IV. Series.
[DNLM: 1. Thyroid Gland--<lrug effects. 2. Thyroid Hormones-physiology. 3. Antithyroid Agents-pharmacology. WI HABIL v. 128 1997/wk 202 p538 1997) QP905.H3 vol. 128 [QPI88, T54) 615¢.74] DNLMIDLC for Library of Congress 96-54721
CIP
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Preface
We were a little bemused when asked to edit this volume in the series Hand­ book of Experimental Pharmacology. Carbimazole for an overactive thyroid (sometimes requiring substitution with propylthiouracil) and thyroxine for hypothyroidism hardly seemed to warrant a monograph in this extensive and well established series of books. Further reflection on the scope of the series, however, suggested that there was a place for a volume which dealt with the broader range of drug effects on the thyroid gland, particularly now we have learned so much more about the molecular mechanisms underlying thyroid hormone synthesis and intracellular action. This is, therefore, not a book on how to treat thyroid disorders (although we believe that it will still be of interest to the practising endocrinologist). We have, instead, aimed to bring together as much information as possible on the effects of drugs and other agents on the thyroid.
The first six chapters provide the physiological and pathological back­ ground necessary to understand the pharmacology contained in the later chapters of the book. Clinical aspects of thyroid diseases and their treatment are succinctly reviewed by Toft in Chap. 1. Scanlon has summarised the regulation of TRH and TSH secretion, so vital to the control of thyroid hormone production, in Chap. 2, and the recent spate of knowledge on the structure and function of the TSH receptor is reviewed by Misrahi and Milgrom in Chap. 3. This receptor could soon be an important target for pharmacological intervention.
Hennemann and Visser consider the physiology of thyroid hormone syn­ thesis and metabolism in Chap. 4, and Stockigt and colleagues have reviewed how thyroid hormones are transported in Chap. 5. Important aspects of drug interference are dealt with in these chapters. At the end of this section, in Chap. 6, Franklyn and Chatterjee have provided an update on the interaction of thyroid hormones with their intracellular receptors, a topic which is essen­ tial for an understanding of the development of thyroid hormone antagonists, covered later in Chap. 13.
The remaining chapters concentrate on various pharmacological agents and their effects on thyroid function. Iodine is essential to thyroid hormone synthesis but also has important pharmacological effects which are discussed by Nagataki and Yokoyama in Chap. 7. Next EI Sheikh and McGregor have summarised the mechanism of action of antithyroid drugs, agents which, after
VI Preface
50 years use, are still used as first line treatment by many endocrinologists dealing with Graves' disease. Chapter 9 by Lazarus deals with the effects of lithium on the thyroid gland, a topic of considerable importance given the number of patients receiving lithium as treatment for manic depression. Per­ haps even more important numerically are the problems associated with amiodarone use, which are extensively reviewed by Wiersinga in Chap. 10. Meier and Burger have summarised in Chap. 11 the effects of other pharma­ cological agents on thyroid function, to complete the discussion of the key drugs which act on the thyroid gland.
Next, in Chap. 12, Gaitan considers the effects of a variety of environmen­ tal agents on thyroid function. It is likely that such agents are still underesti­ mated as a cause of goitre and other thyroid problems. Developments in the production of thyroid hormone antagonists are reviewed by Barlow in Chap. 13, highlighting the potential that such agents may have in treatment in the future. Finally, one of us (Weetman) has discussed the effects of a variety of immunomodulatory agents in autoimmune thyroid disease: again, future de­ velopments in our ability to treat Graves' disease are likely to come from such forms of treatment.
Our thanks are due to all of the authors who have contributed these splendid reviews and who have provided manuscripts of such clarity that our editorial job has been a pleasure. We hope that you will enjoy reading these chapters as much as we did. We are also grateful to Springer-Verlag for supporting this venture, especially Doris Walker, whose ever ready help and skill has guided this book through its production and to Kathryn Watson in Sheffield and William Shufftebotham at Springer-Verlag for excellent secre­ tarial and editorial assistance.
Sheffield and London, u.K. August 1997
ANTHONY WEETMAN
ASHLEY GROSSMAN
BARLOW, J.W., Department of Endocrinology and Diabetes, Ewen Downie Metabolic Unit, Alfred Hospital, Commercial Road, Melbourne, Vic 3181, Australia
BURGER, AG., Departement de Medecine, Hopital Cantonal, Division d'Endocrinologie et Diabetologie, Unite de Thyrolde, Rue Micheli-du-Crest 24, CH-1211 Geneve 14, Switzerland
CHATIERJEE, V.K.K., University of Cambridge, Department of Medicine, Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom
CROWE, T.C., Department of Endocrinology and Diabetes, Ewen Downie Metabolic Unit, Alfred Hospital, Commercial Road, Melbourne, Vic 3181, Australia
FRANKLYN, J.A, Department of Medicine, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom
GAITAN, E., VA Endocrinology Section, Department of Medicine, The University of Misissippi Medical Center, 2500 North State Street, Jackson, MS 39216-4505, USA
HENNEMANN, G., Department Internal Medicine III, University Hospital Dijkzigt, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands
LAZARUS, J.H., University of Wales College of Medicine, Department of Medicine, Llandough Hospital, Penarth, Cardiff CF64 2XX, United Kingdom
LIM, C-F., Department of Endocrinology and Diabetes, Ewen Downie Metabolic Unit, Alfred Hospital, Prahran, Commercial Road, Melbourne, Vic 3181, Australia
MCGREGOR, AM., Department of Medicine, King's College School of Medicine and Dentistry, Bessemer Road, London SE5 9PJ, United Kingdom
VIII List of Contributors
MEIER, C.A, Departement de Medecine, Hopital Cantonal, Division d'Endocrinologie et Diabetologie, Unite de Thyro"ide, Rue Micheli-du-Crest 24, CH-1211 Geneve 14, Switzerland
MILGROM, E., INSERM U 135, Faculte de Medecine de Bicetre, Universite Paris-Sud, 78, rue du General Leclerc, F-94275 Le Kremlin-Bicetre Cedex, France
MISRAHI, M., INSERM U 135, Faculte de Medecine de Bicetre, Universite Paris-Sud, 78, rue du General Leclerc, F-94275 Le Kremlin-Bicetre Cedex, France
NAGATAKI, S., The First Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki 852, Japan
SCANLON, M.F., University of Wales College of Medicine, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, Heath Park, Cardiff CF4 4XN, Wales, United Kingdom
SHEIKH, M. EI, Department of Medicine, King's College School of Medicine and Dentistry, Bessemer Road, London SE5 9PJ, United Kingdom
STOCKIGT, J.R., Department of Endocrinology and Diabetes, Ewen Downie Metabolic Unit, Alfred Hospital, Commercial Road, Melbourne, Vic 3181, Australia
TOFT, AD., Endocrine Clinic, Royal Infirmary, Edinburgh EH3 9YW, United Kingdom
TOPLISS, D.J., Department of Endocrinology and Diabetes, Ewen Downie Metabolic Unit, Alfred Hospital, Commercial Road, Melbourne, Vic 3181, Australia
VISSER, T.J., Erasmus Universiteit Rotterdam, Medical School, Department of Internal Medicine, Postbus 1738, NL-3000 DR Rotterdam, The Netherlands
WEETMAN, AP., The University of Sheffield, Department of Medicine, Clinical Sciences Centre, Northern General Hospital, Sheffield S5 7 AU, United Kingdom
WIERSINGA, W.M., Academisch Ziekenhius bij de Universiteit van Amsterdam, Academisch Medisch Centrum, Meibergdreef 9, Afd. Endocrinologie, Secretariaat F5-171, NL-ll05 AZ Amsterdam Zuidoost, The Netherlands
YOKOYAMA, N., The First Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki 852, Japan
Contents
Introduction: Clinical Aspects of Thyroid Treatment A.D. TOFT................................................... 1
A. Introduction .............................................. 1 B. Choices of Treatment for the Hyperthyroidism of
Graves' Disease ........................................... 2 I. Iodine-131 Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1. Acceptability of Irradiation ......................... 2 2. Gastric Carcinoma ................................. 3 3. Ophthalmopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 4. Calcitonin Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
II. Thyroid Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 III. Antithyroid Drug Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
C. Subclinical Hyperthyroidism ................................ 6 D. Correct Dose of Thyroxine in Primary Hypothyroidism. . . . . . . . . 6 E. Subclinical Hypothyroidism: Treatment or Not? . . . . . . . . . . . . . . . . 7 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
CHAPTER 2
Control of TRH and TSH Secretion M.F. SCANLON. With 2 Figures. . . ........ . . ...... . ....... . ...... 11
A. Introduction .............................................. 11 B. Negative Feedback Action of Thyroid Hormones .............. 11 C. Structure and Actions of TRH .............................. 13 D. Structure and Actions of Somatostatin. . . . . . . . . . . . . . . . . . . . . . . . 14 E. Actions of Neurotransmitters. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 F. Actions of Cytokines and Inflammatory Mediators ............. 20 G. Physiological and Secondary TSH Changes. . . . . . . . . . . . . . . . . . . . 20 References ...... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
x Contents
CHAPTER 3
The TSH Receptor M. MISRAHI and E. MILGROM. With 7 Figures 33
A. Introduction .............................................. 33 B. TSH Receptor Cloning ..................................... 34 C. Structure of the TSHR in the Human Thyroid Gland . . . . . . . . . . . 35 D. Structure of the TSHR in Transfected Cells ................... 37 E. Controversies on Receptor Structure ......................... 38 F. Expression of the TSH Receptor in the Baculovirus System ..... 39 G. Shedding of TSH Receptor Ectodomain in Thyroid and
Transfected Cells .......................................... 40 H. Cellular Expression of the TSH Receptor ..................... 42
I. Polarised Expression in the Thyroid .................... 42 II. Expression in Other Cell Types ........................ 43
I. Intracellular Trafficking of the Receptor ...................... 43 I. Polarized Expression in MDCK Cells ................... 43
II. Receptor Downregulation ............................. 46 J. Structure-Function Relationships ............................ 47
I. Transduction Pathways of the TSH Receptor ............ 47 II. Mutagenesis of Transmembrane and Intracellular Domains
of the TSH Receptor ................................. 48 III. Mutagenesis of the Extracellular Domain of the TSH
Receptor ............................................ 50 K. Gene Structure and Regulation ............................. 52
I. Gene Organisation ................................... 52 II. Chromosomal Localisation and Genetic Mapping ........ 53
1. Structure and Function of TSHR Promoter and 5' Flanking Region . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
L. The TSH Receptor and Pathology ........................... 55 I. Autoimmunity ....................................... 55
1. The TSHR and the Genetics of Graves' Disease ....... 55 2. Epitopes of the TSH Receptor Recognised by
the Auto-antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 II. Mutations of the TSH Receptor in Pathology ............ 57
1. TSH Receptor and Tumorigenesis ................... 57 2. TSHR and Non-immune Hyperthyroidism ............ 58
III. Constitutive Mutations and Model of Receptor Activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
IV. Loss of Function Mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 1. Animal Model .................................... 60 2. Thyroid Resistance to TSH Due to TSHR
Mutations ........................................ 61 M. Conclusions ............................................... 62 References .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Contents
XI
G. HENNEMANN and T.J. VISSER. With 12 Figures ................. 75
A. Thyroid Hormone Synthesis ................................ 75 I. Iodide Transport ..................................... 75
II. Biosynthesis of T4 and T3 ............................. 77 III. Thyroid Peroxidase ......... . . . . . . . . . . . . . . . . . . . . . . . . . . 77 IV. H20 2 Generation ..................................... 78 V. Iodination of Tyrosyl Residues in Thyroglobulin ......... 78
VI. Coupling ofIodotyrosines ............................. 79 VII. Endocytosis of Iodinated Thyroglobulin ................. 80
VIII. Release of T3 and T4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 B. Thyroid Hormone Plasma Membrane Transport ............... 82
I. Studies of Plasma Membrane Thyroid Hormone Transport in Isolated Cells ............................ 82
II. Liver Perfusion Studies ............................... 84 III. (Patho )physiological Significance of Thyroid Hormone
Plasma Membrane Transport: Its Role in the Generation of Low Serum T3 in Non-thyroidal Illness in Man. . . . . . . . . 86
C. Thyroid Hormone Metabolism .............................. 89 D. Deiodination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 E. Characterization of Iodothyronine Deiodinases ................ 94 F. Sulphation ................................................ 98
I. Thyroid Hormone Sulphotransferases ................... 98 II. Deiodination of Iodothyronine Sulphates ...... . . . . . . . . . . 99
III. Occurrence of Iodothyronine Sulphates ................. 100 IV. Possible Role of Iodothyronine Sulphation .............. 102
G. Glucuronidation ........................................... 103 I. Thyroid Hormone UDP-Glucuronyltransferases .......... 104
II. Role of Thyroid Hormone Glucuronidation in Humans............................................. 105
III. Glucuronidation of Iodothyroacetic Acid Analogues ...... 106 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
CHAPTERS
Thyroid Hormone Transport J.R. STOCKIGT, C-F. LIM, J.W. BARLOW, and D.J. TOPLlss. With 7 Figures ............................................... 119
A. Introduction .............................................. 119 B. Serum Binding in Humans.... . ........ ....... ....... . .... . . 120
XII Contents
I. Thyroxine-Binding Globulin. . . . . . . . . . . . . . . . . . . . . . . . . . . 122 1. Normal Structure .................................. 122 2. Inherited Variants ................................. 123 3. Acquired Variants ................................. 123
II. Transthyretin ........................................ 124 1. Normal Structure .................................. 124 2. Inherited Variants ................................. 125
III. Albumin ............................................ 126 1. Normal Structure .................................. 126 2. Inherited Variants ................................. 126
IV. Thyroxine Binding in Other Vertebrates ................ 127 V. Role of Binding Proteins .............................. 128
C. Binding Kinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 I. Binding Kinetics, Capacity and Affinity ................. 128
II. Characterisation of High-Capacity, Low-Affinity Binding ............................................. 131
III. Specific Characterisation of TBG Binding ............... 132 IV. Assay of TBG ....................................... 132
D. Free Hormone Measurement ............................... 133 I. Factors Influencing Validity ........................... 135
1. Radiochemical Purity .............................. 135 2. Protein-Tracer Interactions ......................... 135 3. Dilution Effects ................................... 135 4. Other Factors ..................................... 136
II. Non-isotopic Free T4 Methods ......................... 136 III. Thyroid Hormone-Binding Ratio. . . . . . . . . . . . . . . . . . . . . . . 136
E. Interactions with Competitors ............................... 137 I. Pre-dilution and Co-dilution ........................... 138
II. Estimation of In Vivo Competitor Potency .............. 139 III. In Vivo Kinetics of Competitors . . . . . . . . . . . . . . . . . . . . . . . . 140 IV. Interaction Between Competitors ...................... 141 V. Spurious Competition ................................ 141
VI. Drug Competition at Other Sites. . . . . . . . . . . . . . . . . . . . . . . 142 References .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
CHAPTER 6
Molecular Biology of Thyroid Hormone Action 1.A. FRANKLYN and V.K.K. CHATIERJEE. With 4 Figures 151
A. Introduction .............................................. 151 B. Extranuclear Mechanisms of Thyroid Hormone Action ......... 151
I. Plasma Membrane and Intracellular Transport of Thyroid Hormones ................................... 151
II. Extranuclear Sites of Thyroid Hormone Action .......... 152
Contents XIII
C. Identification of High-Affinity Nuclear-Binding Sites for Thyroid Hormones ........................................ 152
D. Cloning of cDNAs Encoding Nuclear Receptors for T3 ......... 153 E. Recognition of Two Genes Encoding Two Major Classes of
TR ....................................................... 154 F. Thyroid Hormone Response Elements ....................... 155 G. Structural Characteristics of TRs and Identification of
Functional Domains ....................................... 157 I. DNA-Binding Domain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
II. Hormone-Binding Domain ............................ 159 III. Nuclear Localisation ........ . . . . . . . . . . . . . . . . . . . . . . . . . . 159 IV. Dimerisation ........................................ 159 V. Silencing of Basal Gene Transcription by Unliganded
TR ................................................. 161 VI. Transcription Activation .............................. 162
1. Hormone-Dependent Activation of Transcription (AF-2) ............................................ 162
2. Constitutive Transcription Activation (AF-1) .......... 163 H. Role of the TR Splice Variant TRa2 ••••••••••••••••••••••••• 164
I. TRs and Human Disease..... ....... . ....... .......... 164 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
CHAPTER 7
Iodine: Metabolism and Pharmacology S. NAGATAKI and N. YOKOYAMA. With 4 Figures 171
A. Introduction .............................................. 171 B. Iodide Transport and Organification ......................... 172 C. Thyroid Autoregulation .................................... 173
I. Autoregulation in Animals ............................ 173 1. Wolff-Chaikoff Effect and Escape. ......... .......... 173 2. Effects of Graded Doses of Iodide ................... 174
II. Autoregulation in Humans ............................ 175 1. Effects of Moderate Doses of Iodide ................. 176 2. Effects of Excess Iodide in Normal Subjects ........... 178
III. Intracellular Effects of Excess Iodide in Relation to Other Regulators .................................... 180 1. Signal Transduction ................................ 180 2. Expression of HLA Molecules and Other Thyroidal
Proteins .......................................... 180 3. Protein Synthesis .................................. 181 4. Organic Iodinated Lipids ........................... 181 5. Growth Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
IV. Mechanism of Autoregulation. . . . . . . . . . . . . . . . . . . . . . . . . . 182
XIV Contents
1. Acute Inhibitory Effect (Wolff-Chaikoff Effect) ....... 182 2. Mechanism of Adaptation .......................... 183 3. Species Differences in Autoregulation ................ 184 4. Role of TSH in Autoregulation .............. . . . . . . . . 184
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
CHAPTER 8
Antithyroid Drugs: Their Mechanism of Action and Clinical Use M. EL SHEIKH and A.M. MCGREGOR. With 1 Figure ............... 189
A. Introduction .............................................. 189 B. Hyperthyroidism .......................................... 189 C. Pharmacokinetics.......................................... 190 D. Mechanism of Action ...................................... 191
I. Inhibition of TPO .................................... 191 1. Thyroid Hormone Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . 191 2. Drug Action ...................................... 192
II. Immunological Effects ................................ 192 1. Graves'Disease ................................... 192 2. Drug Action ...................................... 193
E. Clinical Use. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 I. Indications .......................................... 194
II. Adverse Effects ...................................... 195 III. Administration and Use. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
1. Graves'Disease ................................... 196 2. Drug Usage with Radioiodine ....................... 202 3. Drug Usage in Pregnancy.......... .. . . ......... .... 202 4. Thyroid Storm .................................... 203
F. Conclusions............................................... 203 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
CHAPTER 9
Effect of Lithium on the Thyroid Gland J.H. LAZARUS. With 2 Figures .................................. 207
A. Introduction .............................................. 207 B. Effect on Thyroid Physiology ............................... 207
I. Iodine Concentration ................................. 207 II. Intrathyroidal Effects ................................. 208
III. Effect on Thyroid Hormone Secretion .................. 208 IV. Effect on Peripheral Thyroid Hormone Metabolism ...... 209
C. Effect on the Hypothalamic-Pituitary Axis .................... 209 D. Lithium and Cell Function. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 E. Immunological Effects on Thyroid Function . . . . . . . . . . . . . . . . . . . 212
Contents XV
F. Effect on Thyroid Hormone Action.... ..... ........... .. .... 213 G. Clinical Effects on the Thyroid .............................. 214
I. Goitre .............................................. 214 II. Hypothyroidism ..................................... 215
III. Hyperthyroidism ..................................... 216 H. Clinical Use in Thyroid Disease ............................. 217 References ..... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
CHAPTER 10
Amiodarone and the Thyroid W.M. WIERSINGA. With 12 Figures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
A. Pharmacology of Amiodarone ......... . . . . . . . . . . . . . . . . . . . . . . 225 I. Physicochemical Properties ............................ 225
II. Pharmacokinetics .................................... 225 1. Absorption and Bioavailability ...................... 226 2. Plasma Kinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 3. Tissue Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 4. Metabolism ....................................... 228 5. Elimination ....................................... 230
III. Pharmacology ....................................... 231 1. Electrophysiological Effects ......................... 231 2. Haemodynamic Effects.... ....... . ............. .... 231
IV. Pharmacotherapy .................................... 231 1. Indications for Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 2. Dosing Schedules .................................. 232
V. Toxicology .......................................... 233 1. Nature of Side Effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 2. Pathogenesis of Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . 234 3. Prevention of Side Effects .......................... 235
B. Effects of Amiodarone on Thyroid Hormone Secretion and Metabolism .............................................. 235
I. Changes in Plasma Thyroid Hormone Concentrations ..... 235 1. Human Studies .................................... 235 2. Animal Studies .................................... 237
II. Changes in Thyroid and Extrathyroidal Tissues .......... 238 1. Peripheral Tissues ................................. 238 2. Thyroid .......................................... 239 3. Pituitary .......................................... 242
III. Changes in Thyroid Hormone Kinetics .................. 243 1. Human Studies .................................... 243 2. Animal Studies .................................... 243
IV. Summary............................................ 244 C. Amiodarone-Induced Thyrotoxicosis and Amiodarone-Induced
III. Pathogenesis ........................................ 250 1. Amiodarone-Induced Hypothyroidism. . . . . . . . . . . . . . . . 250 2. Amiodarone-Induced Thyrotoxicosis ................. 253
IV. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257 1. Amiodarone-Induced Hypothyroidism ............... 257 2. Amiodarone-Induced Thyrotoxicosis ................. 258 3. Amiodarone Treatment in Pregnancy . . . . . . . . . . . . . . . . . 260 4. Amiodarone Treatment of Hyperthyroidism .......... 261
V. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262 D. Amiodarone as a Thyroid Hormone Antagonist ............... 264
I. Hypothyroid-Like Effects of Amiodarone ............... 264 1. Heart ............................................ 264 2. Liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268 3. Pituitary .......................................... 270
II. Amiodarone as a T3 Receptor Antagonist ............... 271 1. Inhibition of T3 Binding to Nuclear T3 Receptors. . . . . . . 271 2. Structure-Function Relationship ..................... 273
III. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
CHAPTER 11
Effects of Other Pharmacological Agents on Thyroid Function c.A. MEIER and A.G. BURGER. With 3 Figures .................... 289
A. Introduction .............................................. 289 B. Effects of Various Drugs on Thyroidal Hormonogenesis ........ 289 C. Effects of Drugs on Thyroid Hormone Metabolism ............ 293
I. Deiodination ........................................ 293 II. Microsomal Oxidation ................................ 295
D. Drug Effects on Cellular and Intestinal Uptake of Thyroid Hormone ......................................... 296
I. Cellular Uptake ............... . . . . . . . . . . . . . . . . . . . . . . . 297 II. Intestinal Absorption ................................. 297
References .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
CHAPTER 12
Effects of Environmental Agents on Thyroid Function E. GAITAN. With 1 Figure ...................................... 301
A. Introduction .............................................. 301 B. Chemical Categories, Sources, Pharmacokinetics, and
Mechanism of Action ...................................... 303
(Goitrin) ......................................... 303 2. Disulphides ....................................... 306
II. Flavonoids .......................................... 306 III. Polyhydroxyphenols and Phenol Derivatives ............. 308 IV. Pyridines ............................................ 310 V. Phthalate Esters and Metabolites ....................... 311
VI. Polychlorinated and Polybrominated Biphenyls .......... 312 VII. Other Organochlorines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
VIII. Polycyclic Aromatic Hydrocarbons ..................... 314 References ................................................... 315
CHAPTER 13
Thyroid Hormone Antagonism l.W. BARLOW, T.c. CROWE, and D.l. TOPLISS. With 4 Figures. . . . . . . . 319
A Introduction .............................................. 319 B. Inhibition of Uptake ....................................... 320
I. Mechanisms of Cell Entry ............................. 320 II. Purification of Membrane-Binding Sites ................. 321
III. Inhibition of Uptake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322 IV. Uptake Inhibition and Hormone Responsiveness ......... 323
C. Cytoplasmic Binding ....................................... 324 I. Role of Cytoplasmic Binding .......................... 324
II. Cytoplasmic Binding and Hormone Responsiveness. . . . . . . 325 III. Pharmacological Antagonism of Cytoplasmic Binding ..... 327
D. Antagonism at the Receptor Level .......................... 328 I. Thyroid Hormone Receptors and the Receptor
Superfamily ......................................... 328 II. Heterogeneity Among Thyroid Hormone Receptors ...... 329
III. Tissue Distribution of Receptors ....................... 331 IV. Receptor Regulation of Tissue Responsiveness. . . . . . . . . . . 331 V. Drug Interactions at the Ligand-Binding Site. . . . . . . . . . . . . 334
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
CHAPTER 14
Immunomodulatory Agents in Autoimmune Thyroid Disease AP. WEETMAN. With 4 Figures ................................. 343
A Introduction .............................................. 343 B. Hormones and Autoimmune Thyroid Disease ................. 343
I. Sex Hormones ....................................... 343 II. Glucocorticoids ...................................... 344
XVIII Contents
III. Thyroid Hormones ................................... 344 C. Toxins and Autoimmune Thyroid Disease .................... 346 D. Trace Elements and Autoimmune Thyroiditis ................. 346 E. Drugs and Autoimmune Thyroid Disease ..................... 347 F. Cytokines and Autoimmune Thyroid Disease ................. 351 G. Immunomodulatory Agents in TAO.. ................. ... .. .. 353
I. Glucocorticoids ...................................... 353 II. Other Immunosuppressive Drugs . . . . . . . . . . . . . . . . . . . . . . . 353
III. Other Treatments .................................... 354 References ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
Subject Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
Introduction: Clinical Aspects of Thyroid Treatment A.D. TOFT
A. Introduction Graves' disease is the most common cause of hyperthyroidism in the United Kingdom, accounting for some 70% of cases. The natural history of the hyperthyroidism in the majority is one of repeated episodes of relapse and remission each lasting several months. It is the minority, probably about 25%, who experience a single episode of hyperthyroidism followed by prolonged remission, and even the spontaneous development of hypothyroidism 10-20 years later (IRVINE et al. 1977). If it were possible to predict the future behaviour of the hyperthyroidism when the patient presented, it would be appropriate to prescribe an antithyroid drug for 18-24 months for those des­ tined for a single episode, and to advise surgery or radioiodine therapy for the remainder. However, despite many ingenious efforts based on factors such as HLA status, presence of thyroid-stimulating hormone (TSH)-receptor anti­ bodies (TRAB) and goitre size, it has not been possible to categorize patients with Graves' disease in respect of outcome with any degree of accuracy and treatment remains empirical.
Standard teaching has been that the initial treatment in patients under 40--45 years of age is with an antithyroid drug with a recommendation for surgery should relapse occur. Older patients are treated with iodine-13l. Of course, management varies from centre to centre and between countries and these differences have been highlighted in recent surveys of practice in Europe and in the United States. For example, the preferred treatment of a 43-year­ old female presenting with hyperthyroidism of moderate severity due to Graves' disease who did not plan further pregnancies was antithyroid drugs (77%) by European physicians but iodine-131 (69%) by their North American counterparts. There was an even greater contrast in choice of therapy when the index case was changed to that of a 19-year-old female. One-third of physicians in the United States regarded iodine-131 as most appropriate, whereas the corresponding figure in Europe was only 4% (GUNOER et al. 1987; SOLOMON et al. 1990). The more liberal use of iodine-131 is finding favour with an increasing number of physicians (FRANKLYN and SHEPPARD 1992), but is permanent hypothyroidism the only significant adverse effect? At the same time there are claims that high remission rates can be achieved by the use of an unusual combination of antithyroid drugs and thyroxine (HASHIZUME
2 A.D. TOFf
et al. 1991). Surgery would seem to be the loser in the face of these two developments.
There is little or no debate about the management of toxic nodular goitre, which is with surgery or iodine-131 depending upon the age of the patient and the presence of significant mediastinal compression. The use of antithyroid drugs should be restricted to preoperative preparation.
It is perhaps surprising that any problems are perceived with the treat­ ment of primary hypothyroidism, which is usually both gratifying and simple. Even the therapeutic difficulties in the patient with concomitant symptomatic ischaemic heart disease have been largely overcome as both angioplasty and coronary artery bypass surgery can be safely undertaken in the presence of untreated or partially treated hypothyroidism. Controversy, however, has arisen following the development of increasingly sensitive assays for TSH, which have raised the question of whether a low serum TSH concentration «0.01 mUll) is an indication of overtreatment when recorded in asymptomatic patients with normal serum concentrations of thyroid hormones. And what are the indications for treatment of subclinical hypothyroidism?
B. Choices of Treatment for the Hyperthyroidism of Graves' Disease I. Iodine-131 Therapy
Those in favour of the more widespread use of iodine-131 therapy would argue that it is cheap, easy to administer and effective as a single dose in the majority of cases. By giving a relatively large dose of 400 MBq, patients will be hypothyroid within a year and subsequent management can pass to the pri­ mary care physician. The initial anxieties about an increase in incidence of post-treatment thyroid carcinoma and leukaemia have evaporated. Further­ more, the gonadal irradiation averages 0.8-1.4 rem, similar to that for a barium enema or intravenous pyelogram, and it has not been possible to show an association between incidental or therapeutic irradiation with iodine-131, even in children and adolescents, and congenital abnormalities in subsequent off­ spring - although the series are small. So why not advocate a policy of iodine- 131 therapy for all non-pregnant patients with Graves' disease? Simply because there are anxieties about this treatment modality which cannot entirely be dismissed, particularly when there are other effective treatment options.
1. Acceptability of Irradiation
There is a heightened public awareness of the dangers of radioactivity as a result of widely reported accidents at nuclear power stations. Of the radionu­ clides used in diagnostic and therapeutic nuclear medicine, iodine-131 pro­ vides the greatest radiation hazard to other individuals who come into contact
Introduction: Clinical Aspects of Thyroid Treatment 3
with the patient. The UK Ionizing Radiation Regulations of 1985 are designed to minimize their exposure (NATIONAL RADIOLOGICAL PROTECTION BOARD 1985) and other similar bodies exist. Because of the resultant disruption so­ cially, domestically and at the workplace, albeit temporary, a significant mi­ nority, even among those over the age of 40-45 years for whom iodine-131 has always been the first choice of treatment, are refusing such an option. Disaffec­ tion with radioactive iodine is likely to increase if the recommendations of the International Commission on Radiological Protection are implemented, limit­ ing the annual dose of radiation for members of the public to 1 mSv (INTERNA­ TIONAL COMISSION ON RADIOLOGICAL PROTECTION 1990). In this circumstance, the patient treated for hyperthyroidism with 400MBq iodine-131 will be ad­ vised to spend less than 11/ zh on public transport in the lst week, to take 3 days off work, to sleep apart from his or her partner for 20 days and to avoid contact closer than l.Om with children aged 11 or less for up to 3 weeks (O'DOHERTY et al. 1993). This is hardly a practical treatment for active men and women in their twenties and early thirties with young families.
2. Gastric Carcinoma
A recent Swedish report analysed cancer mortality in more than 10000 pa­ tients with an average age of 56 years at the time of treatment with iodine-131, and found that there was a significant increased risk of death from cancer of the stomach more than 10 years after exposure (HALL et al. 1992). The prob­ ability of a radiation-induced cancer is proportional to the radiation dose received by the organ in question. It is perhaps not surprising, therefore, that an excess mortality from gastric carcinoma has been demonstrated, as after the thyroid, the stomach receives the greatest amount of radiation following a therapeutic dose of iodine-131 for hyperthyroidism; thyroid cancer does not develop because a relatively large radiation dose either kills or sterilizes the follicular cells.
The latest methods for predicting excess cancer risks following radiation exposure indicate that, for most radiosensitive organs, there will be an increas­ ing risk of attributable cancer with time. This is because, after a latent period of a few years, the pattern of appearance of radiation-induced cancer is thought to follow a constant multiple of the "natural" baseline rates which themselves invariably increase with age. If people are young at the time of exposure, they have simply more life ahead of them in which radiation­ induced cancer can be expressed, so that the cumulative lifetime risk is higher than for someone exposed at an older age. This view, taken together with the Swedish study, provides a cogent argument against reducing the long­ established age threshold for radioiodine treatment for hyperthyroidism in Europe of 40-45 years.
3. Ophthalmopathy
Although a large retrospective study has shown no influence of the type of treatment of the hyperthyroidism of Graves' disease on the clinical course of
4 A.D. TOFT
the ophthalmopathy (SRIDAMA and DEGROOT 1989), most clinicians will cite anecdotal evidence that the eye disease will worsen most often after iodine- 131. This clinical suspicion has been supported by a recent prospective study in which ophthalmopathy developed for the first time or was exacerbated in one­ third of patients treated with iodine-131 and was twice as frequent, and of more severity, than in those treated with antithyroid drugs or surgery (TALLsTEDTet a1.1992). However, serum TSH concentrations were more often raised in the iodine-131-treated patients and subsequently it has been shown that the development of subclinical or overt hypothyroidism following iodine- 131 is associated with the onset or exacerbation of ophthalmopathy (KUNG et al. 1994). Surprisingly, more patients in this study developed ophthalmopathy than experienced an exacerbation of pre-existing disease; and inhibition of the post-radioiodine surge in serum TRAB concentrations with methimazole and thyroxine as "block and replacement therapy" did not influence the natural history of the ophthalmopathy, although corticosteroids have been shown to be beneficial in this respect if given for 3-4 months (BARTALENA et al. 1989).
Unless the ophthalmopathy is severe, when even slight deterioration might result in the need for orbital decompression, the presence of eye disease is not a contraindication to treatment with iodine-131. However, it may be sensible to consider corticosteroids following iodine-131 therapy for 3-4 months in those with mild or moderate ophthalmopathy and to ensure in all patients that prolonged periods of thyroid failure do not occur in the early months after treatment. This would require closer supervision than the normal pattern for review in most centres. It would also be appropriate to advise that smoking is stopped as this is an established risk factor for ophthalmopathy (SHINE et al. 1990).
4. Calcitonin Deficiency
Although intra thyroidal C-cells do not concentrate radioactive iodine, they could be damaged indirectly due to their contiguity to follicular cells. Indeed, both basal and intravenous calcium-stimulated calcitonin concentrations are reduced in patients in whom hyperthyroidism has been treated with iodine-131 (TZANELA et al. 1993). The consequences of long-term calcitonin deficiency are not known but may include osteoporosis. This is particularly relevant as most patients treated with iodine-131 will develop hypothyroidism, and thy­ roxine replacement in a dose sufficient to suppress serum TSH concentrations may be a factor in reducing bone mineral density.
II. Thyroid Surgery
One year after subtotal thyroidectomy for Graves' disease, undertaken by an experienced surgeon, 80% of patients will be euthyroid, 15% will have per­ manent thyroid failure and in 5% operation will have failed to cure the hyperthyroidism (TOFT et al. 1978). These figures flatter to deceive as 50% will
Introduction: Clinical Aspects of Thyroid Treatment 5
be hypothyroid after 25 years (FRANKLYN 1994), and even later recurrence of thyrotoxicosis is well recognized (KALK et al. 1978). Published figures for hypothyroidism may be overestimated unless it has been recognized that thyroid failure occurring in the first 6 months after operation may be tempo­ rary. Neither of the other two treatments for Graves' hyperthyroidism is associated with a scar or a 1 % chance of permanent hypoparathyroidism or vocal cord palsy. Even in the absence of damage to a recurrent laryngeal nerve, significant changes in voice quality may be recorded after subtotal thyroidectomy (KARK et al. 1984), making surgery an inadvisable option for those who depend upon their voice for a living. Surgery does promise the longest period of euthyroidism and is probably the most appropriate treat­ ment for young patients who are poorly compliant with antithyroid drugs, the hope being that if and when thyroid failure or recurrent hyperthyroidism occurs they will be sufficiently mature to adhere to treatment. The consensus is that surgery is indicated as the primary treatment in severely hyperthyroid young patients with large goitres in whom relapse is almost certain after a course of antithyroid drugs.
OI. Antithyroid Drug Therapy
Drugs such as carbimazole and its active metabolite, methimazole, are effec­ tive in controlling hyperthyroidism because they inhibit thyroid hormone production. In patients with hyperthyroidism caused by Graves' disease, these drugs may also have an immunosuppressive action, causing a fall in the serum concentrations of TRAB (WEETMAN et al. 1984). The main disadvantage of antithyroid drug therapy is that the recurrence rate after treatment is stopped varies widely from 25% to 90% (SUGRUE et al. 1980; FRANKLYN 1994). Factors affecting the recurrence rate include dosage and duration of treatment (ALLANIC et al. 1990). One reason for using high doses of antithyroid drugs, which must be combined with thyroid hormone to avoid hypothyroidism, is the belief that their postulated immunosuppressive effect may be dose related. For example, in one study the recurrence rate was 55% in patients treated with an antithyroid drug alone and 25% in patients given combined therapy (ROMALDINI et al. 1983). However, in a large prospective multicentre Euro­ pean trial (REINWEIN et al. 1993), combination therapy was no more effective.
It is the dissatisfaction with these high recurrence rates, following pro­ longed treatment with antithyroid drugs for 18-24 months, which have led many physicians to begin to favour a more liberal age policy for the use of iodine-131. Against this background, the report that in Japanese patients the rate of relapse of hyperthyroidism could be reduced from 35 % to less than 2 % by treatment with methimazole for 18 months, to which thyroxine was added after the first 6 months and continued for 3 years after the antithyroid drug was stopped, could be regarded as the single most important development in the management of Graves' hyperthyroidism for many years (HASHIZUME et al. 1991). The explanation provided for these remarkable results was that by
6 A.D. TOFT
suppressing endogenous TSH secretion with thyroxine, thyroid antigen re­ lease would be inhibited and the serum concentration of TRAB, the cause of the hyperthyroidism of Graves' disease, would fall. If confirmed in other ethnic groups, combined antithyroid drug T4 therapy would become the initial treatment of choice in all patients with Graves' hyperthyroidism, surgery and radioiodine being reserved for that small proportion of patients who relapse. Unfortunately when the study was repeated in a large number of Caucasian patients not only was there no difference in the rate of fall of serum TRAB concentrations between the antithyroid drug alone group and fuat taking combined therapy, but also rates of recurrence of hyperthyroidism were iden­ tical (McIvER et al. 1996).
So on the one hand patients with Graves' disease are fortunate in that they have a choice of treatments, each of which is usually effective in controlling the hyperthyroidism, but on the other hand none is perfect and there is no overall frontrunner. The treatment offered and accepted will continue to depend upon the prejudices of the physician and of the patient and upon the local circumstances such as availability of isotope facilities and the services of an experienced surgeon. The author's prejudice is to reserve iodine-131 therapy for older patients and to favour prolonged courses of antithyroid drugs in younger patients repeated, if necessary, if surgery is declined. It is perfectly reasonable to maintain patients on small doses of an antithyroid drug for many years, recognizing that adverse effects may occur at any time, although usually within 3-6 weeks of starting treatment.
C. Subclinical Hyperthyroidism Patients with normal serum concentrations of thyroid hormones but sup­ pressed TSH in the context of Graves' disease in remission and nodular goitre have tended to be observed until overt hyperthyroidism develops, often after several years. However, there is now evidence that a low serum TSH concen­ tration of itself is a risk factor for atrial fibrillation (FORFAR et al. 1981; SAWIN et al. 1994) and, particularly in the elderly, a case can be made for "nipping it in the bud" by administering iodine-131 and preventing the possibility of future morbidity or even mortality (PARKER and LAWSON 1973).
D. Correct Dose of Thyroxine in Primary Hypothyroidism The advice of the American Thyroid Association in the management of pri­ mary hypothyroidism is that "the goal of therapy is to restore most patients to the euthyroid state and to normalize serum T3 and T4 concentrations" (SURKS et al. 1990). This stance is a consequence of studies which have shown that doses of thyroxine which suppress TSH secretion have more widespread ef-
Introduction: Clinical Aspects of Thyroid Treatment 7
fects such as increasing nocturnal heart rate, shortening the systolic time interval, increasing urinary sodium excretion and serum enzyme activities in liver and muscle and decreasing the serum cholesterol concentration (LESLIE and TOFT 1988). These effects are similar to, but less marked than, those in overt hyperthyroidism. The greatest concern, however, is the possible delete­ rious effect on bone of over-replacement. Significant decreases in bone min­ eral density at various sites have been found in some but in no means all studies of pre- and postmenopausal women receiving long-term thyroxine therapy in doses sufficient to suppress TSH concentrations (ToFT 1994). It is difficult to reconcile the results of the various studies, many of which were small and poorly controlled for important risk factors for osteoporosis such as smoking, insufficient exercise, relative calcitonin deficiency due to thyroidectomy or iodine-131 treatment, previous hyperthyroidism and inad­ equate dietary intake of calcium and vitamin D. The current consensus is that a little too much thyroxine is likely to be only a minor aetiological factor in the development of osteoporosis, if it is a factor at all. Indeed there are those who would question the relevance of minor changes in target organ function in individuals who are asymptomatic, the more so when a recent retrospective study failed to demonstrate an increase in morbidity or mortality in thyroxine­ treated patients with suppressed serum TSH compared to those with normal serum TSH (LEESE et al. 1992), nor is there any evidence of an increased fracture rate (SOLOMON et al. 1993). There is also the important clinical obser­ vation that some patients prefer taking a daily dose of thyroxine of 50 J..Lg in excess of that required to normalize the serum TSH response to thyrotrophin­ releasing hormone (CARR et al. 1988), and there is some evidence for tissue adaptation to thyroid hormone excess (NYSTROM et al. 1989). For practical purposes, therefore, it would seem reasonable to modify the advice of the American Thyroid Association to cater for those patients in whom there will only be a sense of well-being when the serum TSH concentration is undetect­ able, using an assay with a lower limit of detection of 0.01-0.05 mUll. In this circumstance serum free T4 is unlikely to exceed 30pmolll and T3 will be unequivocally normal.
E. Subclinical Hypothyroidism: Treatment or Not? Subclinical hypothyroidism is the rather unsatisfactory term used to describe asymptomatic patients in whom serum thyroid hormone concentrations are normal but TSH elevated. Developing spontaneously and due to autoimmune thyroid disease, it is present in 3 % of the population and in 10% of postmeno­ pausal women. It is commonly found after treatment of hyperthyroidism by surgery, iodine-131 or antithyroid drugs, but may result from the use of medi­ cation such as lithium carbonate or amiodarone.
There has been great interest in the effect of subclinical hypothyroidism and its treatment with thyroxine on circulating lipid concentrations because of
8 A.D. TOFf
the association of overt hypothyroidism with hyperlipidaemia and increased risk of ischaemic heart disease. The results of studies have been conflicting and no clear message emerges (FRANKLYN 1995; KUNG et al. 1995).
Those favouring a pragmatic approach to the management of subclinical hypothyroidism will be most influenced by the knowledge that between 25% and 50% of such patients feel better while taking thyroxine (COOPER et al. 1984; NYSTROM et al. 1988) and by the fact that the annual rate of evolution from subclinical to overt hypothyroidism is approximately 5% (TUNBRIDGE et al. 1981) and may be as high as 20% in patients over 65 years of age (ROSENTHAL et al. 1987). In those patients with minor elevations of serum TSH «lDmU/I) and no goitre, history of thyroid disease or antithyroid peroxidase antibodies, the measurement should be repeated in 3-6 months to determine whether long-term treatment with thyroxine is necessary, because the initial raised concentration may simply reflect recovery from non-thyroidal illness or transient thyroid injury.
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10 A.D. TOFf: Introduction: Clinical Aspects of Thyroid Treatment
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Tzanela M, Thalassinos NC, Nikou A, Philokiproud (1993) Effect of 1311 treatment on the calcitonin response to calcium infusion in hyperthyroid patients. Clin Endocrinol (Oxf) 38:25-28
Weetman AP, McGregor AM, Hall R (1984) Evidence for an effect of antithyroid drugs on the natural history of Graves' disease. Clin Endocrinol (Oxf) 21:163-172
CHAPTER 2
Control of TRH and TSH Secretion M.F. SCANLON
A. Introduction The hypothalamus stimulates thyroid function via thyroid-stimulating hor­ mone (TSH) since hypothyroidism occurs if the hypothalamus is lesioned or diseased, or if the pituitary stalk is transected. This stimulatory hypothalamic control is exerted by thyrotrophin-releasing hormone (TRH), a tripeptide produced by peptidergic neurons and transported along their axons to specialised nerve terminals in the median eminence of the hypothalamus where it is released into hypophyseal portal blood and hence transported to the anterior pituitary gland (JACKSON 1982). Circulating thyroid hormones exert powerful negative feedback inhibitory actions on the thyrotrophs and also on TRH-producing hypothalamic neurons (Fig. 1). In addition, several secondary modulators exert lesser degrees of control over TSH secretion, the net result of which is the maintenance of a steady output of TSH and therefore of thyroid hormones. The neuroregulation of TSH secretion has recently been reviewed in depth (SCANLON and TOFT 1995) which forms the basis for this chapter. The most important secondary modulators are somatostatin and dopamine, both of which inhibit the function of the thyrotrophs, and a­ adrenergic pathways, which are, in general, stimulatory. Other modulators of thyroid function include glucocorticoid hormones, various cytokines and other inflammatory mediators.
B. Negative Feedback Action of Thyroid Hormones Serum TSH in rats is rapidly suppressed to 10% of pretreatment concentra­ tions within 5 h of T3 administration. Further TSH suppression occurs more slowly and only after chronic treatment with T3. The rapid phase of TSH suppression is paralleled by an increase in nuclear T3 content, and serum TSH concentrations rise as nuclear T3levels decline (SILVA et al. 1978). There is an inverse relationship between nuclear T3 receptor occupancy and serum TSH concentrations after acute administration of T3. About half of pituitary nuclear T3 is derived from the intracellular 5'-monodeiodination of thyroxine (T4) , which is a greater fraction than in other tissues; this monodeiodination may be the mechanism by which the thyrotrophs respond to changes in serum T4 concentrations (SILVA and LARSEN 1978).
12
e
Fig. 1. Central pathways in the feedback regulation of TSH secretion. (From SCANLON
and TOFT 1995, with permission)
The major actions of thyroid hormones are to regulate gene expression after binding to specific nuclear receptors. Thyroid hormone receptors are structurally related to the viral oncogene v-erb A and, together with steroid, vitamin D and retinoic acid receptors, form a family of receptor proteins with important structural similarities. Several cDNAs that encode different thyroid hormone receptors (a and {3) have been described. Binding of T3 to a site on the carboxyl-terminal end of the receptor activates the receptor so that the T3-receptor complex binds to specific nucleotide sequences on target genes (EVANS 1988). In thyrotrophs, the activated T3 receptor inhibits trans­ cription of the a-subunit and TSH-f3-subunit genes in proportion to nuclear T3-receptor occupancy.
In addition to this action, thyroid hormones also modulate the expression of the TRH-receptor gene (YAMADA et al. 1992). The number of TRH recep­ tors on thyrotrophs increases in hypothyroidism and can be reduced by thyroid hormone replacement (HINKLE et al. 1981). Conversely, in rat pituitary tumour cells, TRH itself reduces T3-receptor gene expression (JONES and CHIN 1991), receptor number and T3 responsiveness (KAJI and HINKLE 1987), which may represent a further site of feedback interaction between T3 and TRH at the level of the pituitary. Thyroid hormones exert negative feedback actions on the hypothalamus (KAKUCSKA et al. 1992). TRH mRNA increases in the para ventricular nuclei in hypothyroidism and is reduced by thyroid hormone treatment. Furthermore, rats with bilateral lesions of the paraventricular nu­ clei do not show a normal rise of serum TSH and TSH-subunit mRNA after induction of primary hypothyroidism (TAYLOR et al. 1990), an effect that presumably reflects depletion of TRH. These results indicate that the para ventricular nuclei are a target for the action of thyroid hormones in the control of TRH gene expression and release, providing an additional mecha­ nism for thyroidal regulation of TSH secretion (TAYLOR et al. 1990; KANUCSKA et al. 1992; GREER et al. 1993).
Control of TRH and TSH Secretion 13
c. Structure and Actions of TRH
TRH is a weakly basic tripeptide, pyro-Glu-His-Pro-amide which, like other more complex peptides, is derived from post-translational cleavage of a larger precursor molecule (LECHAN et al. 1986). The cDNA sequence of the rat TRH precursor encodes a protein with a molecular size of 29000 daltons that con­ tains five copies of the sequence Glu-His-Pro-Gly (JACKSON 1989). Rat pro­ TRH is processed at paired basic residues to a family of peptides that include TRH and flanking and intervening sequences. These peptides may exert im­ portant intracellular or extracellular actions (Wu 1989), in particular prepro­ TRH-(160-169), which stimulates TSH gene expression (CARR et al. 1992, 1993). There may be preferential processing of pro-TRH to produce different peptides in different brain regions (LECHAN et al. 1986).
Immunoreactive TRH is widely distributed in the hypothalamus with highest concentrations in the median eminence and the so-called "thy­ rotrophic area" or paraventricular nuclei (JACKSON 1982). Lesions of the paraventricular nuclei reduce circulating TSH levels and prevent the increase in serum TSH that occurs in primary hypothyroidism (TAYLOR et al. 1990). TRH and pro-TRH perikarya are present in the parvicellular division of this nucleus (JACKSON and LECHAN 1985), which is the major site of origin of the immunoreactive TRH in the median eminence as opposed to other brain regions such as the tractus solitarius (SIAUD et al. 1987). The TRH gene is also expressed in the anterior pituitary (BRUHN et al. 1994; CROISSANDEAU et al. 1994) and TRH-positive axons are present in posterior pituitary tissue. How­ ever, lesions of the paraventriclar nuclei reduce the content of TRH in both anterior and posterior pituitary tissue, indicating that the hypothalamus is a source of some of the immunoreactive TRH in these areas.
The dominant stimulatory role of the hypothalamus in the control of the thyrotroph is mediated by TRH (JACKSON 1982). The pituitary TRH receptor belongs to the family of seven transmembrane domain, G-protein-coupled receptors. TRH is present in hypophyseal portal blood at physiologically relevant concentrations (SHEWARD et al. 1983) and administration of anti­ bodies to TRH to animals can cause hypothyroidism. Intravenous administra­ tion of 15-500 J1g TRH to normal humans causes a dose-related release in TSH. In normal subjects serum TSH levels increase within 2-5 min, are maxi­ mal at 20-30min and return to basal by 2-3h. Peak serum T3 and T4 levels occur about 3 and 8h, respectively, after TRH administration. In addition to stimulating TSH release, TRH also stimulates TSH synthesis by promoting transcription and translation of the TSH subunit genes, actions that involve calcium influx, activation of phosphatidyl-inositol pathways and protein kinase C (CARR et al. 1991; SHUPNIK et al. 1992; HAISENLEDER et al. 1993). These actions are modulated by cAMP and the pituitary-specific transcription factor, Pit-l (STEINFELDER et al. 1992; MASON et al. 1993; KIM et al. 1994) (Fig. 2).
14
cx1AD
TRH
55 DA2 cx.1AD TRH in TRH desensitisation
! ~ N,/ Ns ~)tJ \ ~ / IP3+ DAG I=l cAMP t icCa++ I - Ca++
I'PK PKC Ex~tosiS
T5H
5'-monodeiodinase
Fig.2. Receptor-mediated actions on the thyrotroph T3reduces the actions of SS, DA, adrenaline and TRH probably via reduced number of corresponding receptors. These actions and the activation of pyroglutamyl aminopeptidase are probably due to binding of the activated thyroid hormone receptor (THR) to relevant parts of the genome. Numbers in parentheses indicate the chromosomal location of the genes for the a and f3 THRs and the a- and f3-subunits of TSH. (From SCANLON and TOFT 1995, with permission)
TRH plays an important role in the post-translational processing of the oligosaccharide moieties of TSH, and hence exerts an important influence on the biological activity of TSH (MAGNER 1990). Full glycosylation of TSH is required for complete biological activity. This provides an explanation for the clinical observation that some patients with central hypothyroidism and slightly elevated basal serum TSH concentrations secrete TSH with reduced biological activity that increases after TRH administration. It is likely that alterations in both hypothalamic TRH secretion and in the response of thyrotrophs to TRH contribute to the variable biological activity of the TSH secreted by patients with different thyroid disorders (MIURA et al. 1989), and those with TSH-secreting pituitary adenomas (GESUNDHEIT et al. 1989).
D. Structure and Actions of Somatostatin Somatostatin (SS) was originally isolated from ovine hypothalamic tissue be­ cause it inhibits GH release from anterior pituitary tissue. Subsequently, SS
Control of TRH and TSH Secretion 15
was found to inhibit TSH secretion in both animals and humans. The structure of the gene encoding SS in both humans (SHEN et al. 1982) and rats (MONTMINY et al. 1984) is now known. SS-producing hypothalamic neurons are found mainly in the anterior periventricular region. About half the SS in the median eminence arises from the preoptic region while the remainder arises from the suprachiasmatic and retrochiasmatic regions. A lower density of SS-producing neurons is present in the ventromedial and arcuate nuclei and also in the lateral hypothalamus (HALASZ 1986). SS is also widely distributed throughout the extrahypothalamic nervous system and other body tissues, where it exerts a wide array of inhibitory actions. It is secreted in two principal forms: a 14- amino-acid peptide and an N-terminal extended peptide (somatostatin-28). Its precursor, preproSS, is a 116-amino-acid peptide (SHEN et al. 1982; GOODMAN et al. 1983) that undergoes differential post-translational processing in differ­ ent tissues to yield varying amounts of the 14- and 28-amino-acid forms of the hormone. Each of these forms is secreted into hypophyseal portal blood in physiologically relevant concentrations (MILLAR et al. 1983).
SS inhibits basal and TRH-stimulated TSH release from rat anterior pitui­ tary cells (VALE et al. 1975), suggesting a dual control system for TSH, stimu­ lation by TRH and inhibition by SS, analogous to that demonstrated for growth hormone: its physiological relevance was established in studies using antisera against SS. Incubation of anterior pituitary cells with anti-SS serum causes increased secretion of TSH (as well as GH), and administration of antiserum to rats increases basal serum TSH concentrations and the serum TSH responses to both cold stress and TRH (ARIMURA and SCHALLY 1976; FERLAND et al. 1976). In humans, SS administration reduces the elevated serum TSH concentrations in patients with primary hypothyroidism, reduces the serum TSH response to TRH, abolishes the nocturnal elevation in TSH secretion, and prevents TSH release after administration of dopamine antago­ nist drugs. SS-14 and -28 exert equipotent effects on TSH release (RODRIGUEZ­ ARNAO et al. 1981). Furthermore, GH administration in humans decreases basal and TRH-stimulated TSH secretion (LIPPE et al. 1975), probably because of direct stimulatory effects of GH on hypothalamic SS release (BERELOWITZ et al. 1981). In patients with pituitary disease, TSH secretory status correlates inversely with GH secretory status (COBB et al. 1981). Despite these potent acute inhibitory effects of SS on TSH secretion in humans, long-term treat­ ment with SS or the long-acting analogue, octreotide, does not cause hypothyroidism (PAGE et al. 1990), presumably because the great sensitivity of the thyrotrophs to any decrease in serum thyroid hormone concentrations overrides the inhibitory effect of SS in the long term.
SS binds to at least five distinct types of specific, high-affinity receptors (SSTR 1 to 5) in the anterior pituitary, brain and other tissues (GONZALES et al. 1989; KIMURA 1989). The receptor subtypes differ in binding specifities, molecular weight and linkage to adenylate cyclase. The pituitary SS receptors (predominantly SSTR 2 and SSTR 5) are negatively coupled to adenylate cyclase through the inhibitory subunit of the guanine nucleotide regulatory
16 M.F. SCANLON
protein, conventionally termed Ni, a mechanism that mediates at least some of the inhibitory actions of this neuropeptide. However, SS also acts indepen­ dently of cAMP by reducing calcium influx and inducing hyperpolarization of membranes through conventional G protein linkage to calcium and potassium channels, respectively (NILSSON et al. 1989) (Fig. 2).
E. Actions of Neurotransmitters An extensive network of neurotransmitter neurons terminates on the cells bodies of the hypophysiotropic neurons, and within the interstitial spaces of the median eminence, where they regulate neuropeptide release into hypo­ physeal portal blood. In addition, dopamine (and possibly other neurotrans­ mitters) is released directly into hypophyseal portal blood and exerts direct actions on anterior pituitary cells, particularly as the major physiological in­ hibitor of prolactin release, but to a lesser extent as a physiological inhibitor of TSH release.
As a consequence of the specialised anatomical arrangements within the hypothalamus, each of the hypophysiotropic neuronal systems that regulate TSH secretion (TRH, SS and dopamine) are, in turn, influenced by networks of other neurons that project from several brain regions. Without these projec­ tions, basal TSH secretion (in rats and presumably in humans) and feedback regulation by thyroid hormones is relatively normal, suggesting that basal TRH secretion is regulated by intrinsic hypothalamic function interacting with pituitary and thyroid hormones. In contrast, circadian rhythms of TSH and pituitary-thyroid changes in response to stress and cold exposure (in lower animals) are mediated by nerve pathways that project to the medial basal hypothalamus (FUKUDA and GREER 1975).
The principal systems that influence tuberoinfundibular neurons contain a bioamine neurotransmitter (dopamine, serotonin, histamine or adrenaline), although several other neuropeptides and amino acid neurotransmitters may playa role. Virtually all the dopaminergic, nor adrenergic and serotoninergic pathways that project to the hypothalamus arise from groups of nuclei located in the midbrain. Two dopaminergic systems exist within the hypothalamus: one, entirely intrinsic to the hypothalamus, arises in the arcuate nuclei, and the other projects from the midbrain. Histaminergic pathways are intrinsic to the hypothalamus, whereas adrenergic pathways arise from cell groups in the midbrain, although an intrinsic hypothalamic noradrenergic system also may exist. Opioid and y-aminobutyric acid systems are mainly intrinsic to the hypothalamus. Cholinergic systems appear to play little part in the neuro­ regulation of TSH secretion (MORLEY 1981).
In view of the complexity of these interacting neuronal networks, it is hardly surprising that neuropharmacological attempts to dissect the relative contributions of different neurotransmitter systems to the neuroregulation of TSH secretion have proved difficult. Furthermore, certain pathways have been
Control of TRH and TSH Secretion 17
studied extensively in rats yet hardly at all in humans, and the lack of availabil­ ity of specific neuropeptide antagonists has limited study of the direct physio­ logical relevance of many of these molecules. Despite these problems consensus views have developed concerning the roles of several neurotrans­ mitter pathways.
Studies using central neurotransmiter agonist and antagonist drugs have indicated the existence of stimulatory a-noradrenergic and inhibitory dopam­ inergic pathways in the control of TSH secretion in rats. a-Adrenergic agonists injected systemically or into the third ventricle stimulate TSH release, and a­ adrenergic antagonists or catecholamine-depleting drugs block TSH responses to cold (MORLEY 1981). More precisely, it appears that ~ pathways are stimu­ latory, whereas a) pathways are inhibitory (KRULICH 1982). It has been as­ sumed from such in vivo studies that these neurotransmitter effects are mediated by the appropriate modulation of the release of TRH, SS or both, into hypophyseal-portal blood. A clear example of this is that the acute TSH release that follows cold stress in rats can be abolished by pretreatment with either anti-TRH antibodies or a-adrenergic antagonists, suggesting that ad­ renergically stimulated TRH release mediates this effect (JACKSON 1982).
The results of in vitro studies using rat hypothalamic tissue, however, are not in keeping with this attactive and simple hypothesis. For example, dopam­ ine and dopamine-agonist drugs stimulate both TRH and SS release from rat hypothalamus, acting through the DAz class of dopamine receptors (LEWIS et al. 1987,1989). This may reflect a general action of DAz receptors to mediate enhanced neuropeptide release at the level of the median eminence, in con­ trast to the usual inhibitory action of DAz agonists at the level of the anterior pituitary.
Although little precise knowledge exists regarding central mechanisms, it is clear that dopamine and adrenaline exert opposing actions on TSH release directly at the anterior pituitary level. Furthermore, both these molecules are present in rat hypophyseal portal blood at higher concentrations than in peripheral blood and at concentrations that could exert physiological actions on the thyrotrophs (BEN-JONATHAN et al. 1977; JOHNSTON et al. 1983). Dopam­ ine inhibits TSH release from rat (FOORD et al. 1980) and bovine (COOPER et al. 1983) anterior pituitary cells in a dose-related, stereospecific way, and there is striking parallelism between the inhibition of TSH and prolactin by dopamine and dopamine-agonist drugs (FOORD et al. 1983). As with prolactin, this inhibi­ tory action on TSH release is mediated by DA2 receptors (FOORD et al. 1983) that are negatively coupled to adenylate cyclase. TSH release by thyrotroph cells from hypothyroid animals is more sensitive to the inhibitory effects of dopamine, which may reflect increased DAz receptor number rather than affinity (FOORD et al. 1984). In contrast, the sensitivity of prolactin to the inhibitory effects of dopamine is reduced in lactotroph cells from hypothyroid animals (FOORD et al. 1984, 1986), a phenomenon that may con­ tribute to the hyperprolactinaemia that occurs in some patients with primary hypothyroidism.
18 M.F. SCANLON
Evidence from in vitro studies using rat anterior pituitary cells suggests that TSH may specifically regulate its own release through the induction of DA2 receptors on the thyrotroph cells (FOORD et aL 1985), perifused cells showing little dopaminergic sensitivity due to rapid dispersion of locally re­ leased TSH. These data indicate a mechanism for the ultrashort-loop feedback control of TSH secretion that is dependent on the functional integrity of the hypothalamo-pituitary axis and consequent catecholamine supply (Fig. 2).
In addition to its acute inhibitory effects on TSH secretion in vitro, dopamine also decreases the levels of a-subunit and TSH-,B-subunit mRNAs and gene transcription by up to 75% in cultured anterior pituitary cells from hypothyroid rats. These effects occur within a few minutes and can be reversed by activation of adenylate cyclase with forskolin (SHUPNIK et aL 1986). Similar actions of dopamine have been described in relation to prolactin gene expression.
In contrast to dopamine, adrenergic activation stimulates TSH release by cultured rat and bovine anterior pituitary cells in a dose-related stereospecific fashion. This effect is mediated by high-affinity, ~-adrenoreceptors (PETERS et aL 1983a; KUBANSKI et aL 1983; DIEGUEZ et aL 1984), and both ~­ adrenoreceptors and ~-receptor-mediated TSH release are reduced in cells from hypothyroid animals (DIEGUEZ et aL 1985). Quantitatively, the adrener­ gic release of TSH is almost equivalent to that induced by TRH (DIEGUEZ et aL 1984). Together, at maximal dosage, these two agents have additive effects on TSH release, indicating activation of separate intracellular pathways. It is likely that dopamine and adrenaline exert their direct actions on the thyrotrophs by opposing actions on cAMP generation, with DA2 receptors being negatively linked to adenylate cyclase and a1-adrenoreceptors being positively linked (Fig. 2).
In humans, it is well established that dopamine has a physiological inhibi­ tory role in the control of TSH release, and some data suggest a stimulatory a­ adrenergic pathway. In contrast to the situation in animals, evidence for direct effects of dopaminergic and adrenergic manipulation on TSH release by nor­ mal human pituitary cells is lacking. Data from the use of dopamine, dopamine agonists and specific dopamine-receptor antagonist drugs such as domperidone, which does not penetrate the blood-brain barrier to any appre­ ciable extent, suggest that dopamine-induced decreases in TSH secretion are a direct pituitary or median eminence action mediated by the DA2 class of dopamine receptor (BURROW et aL 1977; SCANLON et aL 1977, 1979).
The dopaminergic inhibition of TSH release varies according to sex, thy­ roid status, time of day and prolactin secretory status. TSH release after endogenous dopamine disinhibition with dopamine-receptor-blocking drugs, such as metoclopramide and domperidone, is greater in women than in men (SCANLON et aL 1979). It is assumed that oestrogens determine this effect, but the mechanism of action is unknown. The dopaminergic inhibition of TSH release, like the stimulation of TSH release by TRH, is also greater in patients
Control of TRH and TSH Secretion 19
with mild- or subclinical hypothyroidism than in normal subjects or severely hypothyroid patients (SCANLON et al. 1980a). The mechanisms that underlie this biphasic relationship between the dopaminergic inhibition of TSH release and thyroid status are not known, but data from in vitro studies of anterior pituitary cells from hypothyroid rats suggest an increase in dopamine-receptor capacity rather than affinity (FOORD et al. 1984). Also, the concentration of dopamine in hypophyseal portal blood of thyroidectomised rats is greater than that of sham-operated rat. This is due to increased activity of tyrosine hydroxy­ lase in the median eminence, an effect that can be reversed by thyroid hor­ mone replacement (REYMOND et al. 1987; WANG et al. 1989). In addition to its effects on the release of TSH, dopamine also inhibits the release of a-subunit and TSH-,B-subunit, the greatest effect occurring in patients with primary hypothyroidism (SCANLON et al. 1981; PETERS et al. 1983b).
Only limited data are available on the adrenergic control of TSH release in humans. a-Adrenergic blockade with phentolamine, which does not readily cross the blood-brain barrier, or with thymoxamine, which does, inhibits the serum TSH response to TRH (ZGLICZYNSKI and KANIEWSKI 1980) and reduces but does not abolish the nocturnal rise in TSH secretion (VALCAVI et al. 1987). Overall, these data suggest a small stimulatory role for endogenous adrenergic pathways in TSH control in humans. The catecholaminergic control of TSH secretion appears to act as a fine-tuning mechanism rather than being of primary importanc